Field of the Invention
The invention relates generally to compositions and methods for altering the negative effects and disease progression of poly-glutamate associated diseases, such as Huntington's disease.
Description of the Related Art
Huntington's disease is an inherited disease that causes the progressive breakdown (degeneration) of nerve cells in the brain, resulting in a cognitive and motor function decline [1, 2]. The aggregation of a mutant Huntingtin protein (Htt) in cells alters protein function and gene regulation, which causes movement, thinking (cognitive) and psychiatric disorders along with neuronal death. Most people with Huntington's disease develop signs and symptoms in their 20's or 30's, but the onset of disease may be earlier or later in life, with a patient's death typically occurring within 10-15 years of diagnosis. A juvenile form of Huntington's occurs in about 6% of patients characterized by rapid onset of symptoms and disease progression beginning in early childhood.
The genetic mutation that causes Huntington's disease is found in repeats of the amino acid glutamine (Q) near the amino terminus of the Huntingtin protein, called HttpolyQ or HttpQ. The number of repeats is generally predictive of the age of onset and progression rate in the subject. Repeats of more than 38 Q's (SEQ ID NO: 32) result in Huntington's Disease pathology. The function of the Huntingtin protein is not well characterized, but it appears to be involved in transport functions of vesicles containing neurotransmitters and other molecules needed for cell and tissue function [3, 4]. Although the mutation is found in all cells, Huntington's disease manifests predominantly in the brain.
Aggregation of HttpQ leads to abnormal and arrested degradation of the Huntingtin protein and the production of toxic degradation products that appear to enter the nucleus of the cell and play a role in gene dysregulation [5]. HttpQ fragments in the nucleus bind to transcriptional regulatory proteins that drive cellular functions [4-6]. Furthermore, toxic fragments of HttpQ that accumulate in the nucleus alter gene expression by direct binding to DNA and by altering chromatin structure [7, 8]. Several lines of evidence demonstrate that a caspase 6-cleaved fragment accumulates in the nucleus and blockage of Capsase 6 cleavage eliminates generation of the toxic nuclear fragment resulting in the absence of disease in HttpQ animals [9-11]. The patterns of gene dysregulation are well characterized and consistent in cell-based systems, in animal models that exhibit HttpQ aggregation and in patient samples taken at autopsy. The gene families mostly affected are those that regulate protein synthesis and degradation, protein folding (also known as heat shock pathways), and mitochondrial function that provide power to cells.
The subsequent loss of neurons that regulate motor function and cognition leads to progressive dementia and loss of motor control. Thus, there is a need for compositions and methods that modify the degradation process. In particular, disease modification therapy must demonstrate the ability to prevent gene dysregulation and HttpQ aggregation, which appears to be a primary factor in disease progression. To date, no disease-modifying therapeutic agents have been identified that prevent aggregation of HttpQ and modify gene dysregulation. Conventional medications and treatments lessen symptoms of movement and psychiatric disorders. For example, the only FDA approved drug for Huntington's disease (Xenazine®) provides temporary relief of chorea, a diagnostic part of motor movement dysfunction that led to the initial characterization of this disease.
The present disclosure seeks to fulfill this need and provide further related advantages.